Adverse local tissue reactions (ALTRs) in patients with total hip replacements (THRs) are on the rise and are on par with periprosthetic infection as a major reason for THR failure. Corrosion products generated within modular junctions of the implants lead to ALTRs; thus, modular junction corrosion is one of the most urgent topics in joint arthroplasty. The long term goal of this work is to reduce corrosion damage and increase longevity of THRs by optimizing material quality and surface finish. It is the objective of this application to identify modes of corrosion that lead to ALTRs and how they depend on material, implant design, surgical implantation and patient factors. The central hypothesis is that specific corrosion modes can be inhibited by a homogeneous implant alloy with moderate grain size and optimal synergism between global and local implant design factors. The rationale underlying the proposed research is that, determining the material microstructure and surface topography that minimizes corrosion and micromotion will improve modular junctions and reduce implant failure. We have three specific aims: 1) Identify the material, implant design, surgical implantation and patient factors that most significantly reduce corrosion damage in modular junctions using a) retrieval analysis and b) multiscale finite element analysis (FEA); 2) Determine how alloy microstructure affects specific corrosion modes under a) cyclic load, and b) additional micromotion (fretting), and experimentally and computationally simulate the effect of ceramic head intervention on the corrosion and mechanical behavior of these alloys; and 3) Determine how specific modes of corrosion and subsequent corrosion products influence the occurrence, extent and type of ALTRs (macrophage or lymphocyte dominated). Under aim 1, we will quantify the extent of corrosion damage on retrieved THRs, and use previously developed multiscale FEA to determine the material, implant design and surgical implantation factors that minimize corrosion damage, given differences in the patient. Under aim 2, material samples prepared from the retrieved implants will be used in crevice- and fretting-corrosion tests to determine the effect of material microstructure on metal ion release. Experimental tests and FEA will be used to investigate the consequences of surgical intervention with ceramic femoral heads on damaged stem tapers. Under aim 3, tissue samples and implant surfaces from patients with macrophage and lymphocyte dominated ALTRs will be analyzed and compared to well-functioning (postmortem) controls. The experimental approach is innovative because it uses actual implant material samples, applies more relevant loads and motions which can only be derived by multiscale FEA, and analyzes the biological impact of corrosion modes using tissue samples from the same retrieved implants. The proposed research is significant because it will collectively fill a knowledge gap on how corrosion in modular junctions leads to ALTRs. Ultimately this knowledge has the potential to drive new manufacturing, quality control and preclinical testing methods for THRs, increasing implant life time and improving the well-being of THR patients.